Lymph nodes link sex-biased immune aging to compromised antigen recognition

A diverse naive CD8 T cell repertoire is essential to provide broad protection against infection and cancer. Aging diminishes naive T cells, reducing potential diversity and leading to lymph node contraction. Here, we revealed that this decline occurs earlier in males, resulting in significant sex differences in immunity during middle age. Earlier in life, naive CD8 T cells in males become virtual memory cells prone to premature senescence. Due to androgen-driven thymic atrophy in males, naïve CD8 T cells are insufficiently replenished. Therapeutic thymus rejuvenation via testosterone ablation restored naive CD8 T cells in lymph nodes of middle-aged male mice, leading to enhanced tumor recognition. These findings show the crucial role of sex and age on lymph node T cell repertoires and suggest potential strategies to restore immune function in males during aging.